Abstract 1645: JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division

Abstract Background: Aurora kinase A (AURKA), a crucial mitotic regulator, is frequently dysregulated in a wide range of cancers and contributes to clinical aggressiveness and poor patient survival. Abnormally activated AURKA promotes tumorigenesis through enhancing cancer cell proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal, rendering it an attractive therapeutic target. We have developed JAB-2485, a highly selective small-molecule AURKA inhibitor. Methods: Biochemical and cell-based assays were performed to determine the IC50 of JAB-2485 on Aurora kinase family members. Fluorescence activated cell sorting (FACS) and caspase 3/7 assay were performed to detect JAB-2485-induced cell cycle arrest and apoptosis, respectively. The CellTiter-Glo assay was performed to evaluate the effect of JAB-2485 in multiple cancer cell lines. Finally, the antitumor effect of JAB-2485 either as a single agent or in combinations was investigated in tumor cell line-derived xenografts. Results: JAB-2485 is potent and highly selective on AURKA, with IC50 of 0.33nM and around 1700-fold selectivity over AURKB. Following treatment of JAB-2485, the level of AURKA phosphorylation as a pharmacodynamic marker was significantly decreased in a dose-dependent manner. As a single agent, JAB-2485 inhibited in vitro proliferation of small cell lung cancer (SCLC), triple-negative breast cancer (TNBC) and neuroblastoma cell lines along with induced G2/M cell cycle arrest and apoptosis, and significantly inhibited in vivo tumor growth on SCLC and neuroblastoma xenografts. Furthermore, JAB-2485 showed strong synergy with cisplatin and paclitaxel in SCLC and TNBC animal models, respectively. Conclusions: Taken together, preclinical results provide robust evidence supporting further evaluation of JAB-2485 both as a single agent and in combinations for treatment of various types of cancers. A Phase 1/2a clinical trial of evaluating JAB-2485 in adult patients with advanced solid tumors is enrolling patients in the US (NCT05490472). Citation Format: Guiqun Yang, Yanping Wang, Haijun Li, Mingming Chen, Yiwei Lin, Xin Sun. JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1645.